Abstract
Sunitinib malate is a multi-targeted tyrosine kinase inhibitor used extensively for treatment of human tumors. However, cardiovascular adverse effects of sunitinib limit its clinical use. It is pivotal to elucidate molecular targets that mediate sunitinib-induced cardiotoxicity. Sirtuin 3 (Sirt3) is an effective mitochondrial deacetylase that has been reported to regulate sensitivity of different types of cells to chemotherapies, but roles of Sirt3 in sunitinib-induced cardiotoxicity have not been investigated. In the present study, we established wild type, Sirt3-knockout, and Sirt3-overexpressing mouse models of sunitinib (40 mg kg−1 day−1 for 28 days)-induced cardiotoxicity and examined cardiovascular functions and pathological changes. We further cultured wild type, Sirt3-knockout, and Sirt3-overexpressing primary mouse cardiac pericytes and analyzed sunitinib (10 μMol for 48 h)-induced alterations in cellular viability, cell death processes, and molecular pathways. Our results show that sunitinib predominantly induced hypertension, left ventricular systolic dysfunction, and cardiac pericyte death accompanied with upregulation of Sirt3 in cardiac pericytes, and these cardiotoxicities were significantly attenuated in Sirt3-knockout mice, but aggravated in Sirt3-overexpressing mice. Mechanistically, sunitinib induced cardiac pericyte death through inhibition of GSTP1/JNK/autophagy pathway and Sirt3 interacted with and inhibited GSTP1, further inhibiting the pathway and aggravating sunitinib-induced pericyte death. Conclusively, we demonstrate that Sirt3 promotes sensitivity to sunitinib-induced cardiotoxicity via GSTP1/JNK/autophagy pathway. Our results suggest Sirt3 might be a potential target for developing cardioprotective therapies for sunitinib-receiving patients.
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Acknowledgements
Thanks to Dr. Xiao Wu and Na Li (The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China) for technical support in use of digital confocal microscopy core facility. This work was supported by the State Key Program of National Natural Science Foundation of China 81530014; National Key R&D Plan of China 2017YFC1700502; National Natural Science Foundation for Young Scientists of China 81700366; Key R&D project of Shandong Province 2017GSF18137.
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Yang, Y., Li, N., Chen, T. et al. Sirt3 promotes sensitivity to sunitinib-induced cardiotoxicity via inhibition of GTSP1/JNK/autophagy pathway in vivo and in vitro. Arch Toxicol 93, 3249–3260 (2019). https://doi.org/10.1007/s00204-019-02573-9
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DOI: https://doi.org/10.1007/s00204-019-02573-9